Ubiquitin-like proteins (Ubls) are a growing family of post-translational modifiers that are involved in a diverse array of biological processes. Although Ubiquitin is one of the most well-understood Ubl, several others are now understood to serve many important cellular functions, including: small ubiquitin-like modifier (SUMO), interferon-stimulated gene-15 (ISG15; also known as ubiquitin cross-reactive proteins, UCRP), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8, also called Rub1 in S. cerevisiae), human leukocyte antigen F associated (FAT10), autophagy-8 (Apg8) and -12 (Apg12), Fau ubiquitin-like protein (FUB1), MUB (membrane-anchored UBL), ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe).
Protein-protein interactions mediated by mono-Ubl (ubiquitin and ubiquitin-like proteins) or poly-Ubl modifications are among the most important signalling and regulatory mechanisms that control nearly every aspect of cellular function (1). However, an effective approach to distinguishing poly-Ubl chain mediated from mono-Ubl mediated cellular functions is lacking. In addition to proteasome inhibitors, a small molecule was identified that binds to and alters the conformation of polyubiquitin chains such that their interactions with the proteasome are inhibited (15). However, the negative charge of this small molecule prevents its translocation into cells. Therefore, the identification of inhibitors ubiquitin and ubiquitin-like dependent protein-protein interaction would be useful to study the role of ubiquitination in cellular processes, and for developing therapeutics for viral infection, cancer and other diseases.